Case 23-2006 — A 36-Year-Old Man with Numbness in the Right Hand and Hypertension
http://www.100md.com
《新英格兰医药杂志》
Presentation of Case
Dr. Joanna J. Wykrzykowska (Medicine): A 36-year-old man was admitted to the hospital because of a mass in the right adrenal gland. The patient had been well until seven months before admission, when numbness developed in his left arm, one week after he had been in a motor vehicle accident. He saw a chiropractor, who ordered magnetic resonance imaging (MRI) of his cervical spine, which disclosed a cystic lesion in the medulla. During the evaluation he was noted to have hypertension. Atenolol and nortriptyline were prescribed, and three and a half weeks before admission, he was referred to the surgical clinic of this hospital.
At that time, he reported profuse sweating at night (requiring a change of sheets), palpitations three to five times per day, and insomnia. On examination, the blood pressure was 170/110 mm Hg. MRI of the abdomen three weeks before admission revealed a right adrenal mass, 2.3 by 1.9 cm, with homogeneous enhancement in the arterial phase. There was a complex cyst, 2 by 1 cm, in the left kidney with enhancing septations. There were multiple lesions — apparently hemangiomas — in the liver that appeared bright on T2-weighted images, the largest being 2.4 by 2 cm. metaiodobenzylguanidine (MIBG) scanning on the same day showed a focus of increased radiotracer uptake in the right upper quadrant of the abdomen, superior and medial to the right kidney. The results of routine blood and urine chemical tests and a complete blood count were normal. Urine and serum catecholamine levels are shown in Table 1. MRI of the brain one week later disclosed a right medullary tumor, 1.3 cm in diameter, with a central cystic component that contained a small enhancing nodule along the posterior wall and a solid, nonenhancing component that was isointense relative to brain tissue on T1-weighted and T2-weighted images.
Table 1. Catecholamine Levels.
Twelve days before admission the patient's blood pressure was 190/120 mm Hg. Treatment with terazosin and phenoxybenzamine was begun. Five days before admission, nerve-conduction studies and needle electromyographic examination of the left deltoid, biceps, and flexor carpi radialis were normal. A left cervical radiculopathy could not be ruled out since the patient could not tolerate a full examination including cervical paraspinal muscles. One week later he was admitted to this hospital.
An appendectomy had been performed at the age of 12 years, at which time hypertension was noted; subsequent evaluation disclosed a left adrenal pheochromocytoma, which was resected. The patient received no further medical care until he had a motor vehicle accident. He had no allergies. He smoked half a pack of cigarettes per day and drank alcohol. His mother had polycystic kidney disease. His father had had hypertension since his 50s. His siblings (a 32-year-old sister and a twin brother) and his 15-year-old daughter were healthy. His paternal grandmother had died of a heart attack in her 60s, and his paternal grandfather had died of a stroke in his 70s. His maternal grandfather had died of emphysema. His maternal grandmother had died at the age of 90.
On examination the patient was an anxious-appearing young man. The blood pressure was 145/100 mm Hg and the pulse 64 beats per minute. There was no plethora or proptosis. The thyroid was normal in size and consistency. The heart and lungs were normal. The abdomen was soft and nontender without organomegaly or palpable masses. There was no peripheral edema. Neurologic examination revealed that the strength was 4/4 in the hands and legs, with good muscle bulk, slightly asymmetric reflexes (1+ on the right and 2+ on the left), and decreased proprioception and sensation to touch and temperature in the left arm but no dysmetria. Ophthalmologic examination showed a right retinal hemangioma in the superotemporal periphery, with a large vein leading into it.
Results on routine blood chemical tests and a complete blood count were normal. MRI of the spine revealed a small focal area of enhancement posterior to the spinal cord just to the right of the midline at the level of the T12 vertebral body; the remainder of the examination was normal.
Terazosin was discontinued; increasing doses of phenoxybenzamine were administered, with intravenous normal saline. On the 14th hospital day the blood pressure was 146/80 mm Hg. Phenoxybenzamine was discontinued, and intravenous hydrocortisone was begun; a procedure was performed.
Differential Diagnosis
Dr. Othon Iliopoulos: May we see the imaging studies?
Dr. R. Gilberto Gonzalez: MRI of the abdomen revealed a 2-cm mass located just above the right kidney in the expected location of the adrenal gland. On axial images we noted multiple cystic abnormalities in the liver as well as in the kidney, one of which was complex and enhanced with contrast material (Figure 1A). Nuclear-medicine scanning (Figure 1B) after the administration of MIBG, which is avidly taken up by tissues that secrete catecholamines, showed an area of uptake inferomedial to the liver and superior to the right kidney. MRI of the brain revealed a cystic mass in the dorsal medulla, the posterior aspect of which enhanced intensely after administration of contrast material (Figure 1C and 1D).
Figure 1. Radiologic Images.
MRI of the abdomen three weeks before admission (Panel A) revealed multiple bright lesions in the liver (curved arrow) and kidneys (straight arrows) on T2-weighted images. A posterior view from the MIBG scintigraphic scan (Panel B) demonstrates abnormal uptake in the right upper quadrant of the abdomen below the liver (arrow). MRI of the brain (Panel C) revealed a cystic mass in the dorsal medulla (arrow), with a posterior nodule that enhanced intensely after the administration of contrast material (Panel D, arrow).
Dr. Iliopoulos: This 36-year-old man with a childhood history of pheochromocytoma presented with clinical manifestations of elevated catecholamine levels. Plasma metanephrine and normetanephrine levels are 97 percent sensitive and 96 percent specific for the identification of pheochromocytoma in patients with a genetic predisposition to pheochromocytoma.1,2 Thus, this patient's clinical characteristics are associated with a high probability of recurrent pheochromocytoma. To identify the location of his pheochromocytoma, MIBG scanning was performed. When the sensitivity and specificity of different imaging methods for pheochromocytoma have been compared,3 MIBG nuclear scanning appears to have the highest sensitivity (95 percent) and specificity (97 percent); the results are similar to those of MRI. The advantage of MIBG scanning over MRI is that it offers a total-body survey for the detection of pheochromocytoma. In this patient, both MRI and MIBG imaging clearly identified a pheochromocytoma in the right adrenal gland; this recurrence of pheochromocytoma raised the possibility of an underlying hereditary condition and prompted us to conduct a genetic evaluation.
Ms. Gayun Chan-Smutko: As part of the genetic-counseling process for this family, a four-generation pedigree was obtained (Figure 2). Based on this information, the family history was apparently not a contributor to the differential diagnosis. Despite the absence of a clear familial syndrome, five distinct autosomal dominant hereditary syndromes with pheochromocytoma as a component tumor need to be considered (Table 2).4,5,6,7 In all these syndromes, between 5 and 50 percent of patients have no family history of pheochromocytoma. Several factors can contribute to the absence of a family history: a new mutation that occurred spontaneously during gametogenesis in one of the parents, a germ-line mosaicism in one of the parents, or a new mutation in the embryo. Reduced penetrance (in which a proportion of persons carrying a mutation express no features of the expected phenotype) and variable expression (in which the degree of severity of symptoms differs among family members) can also lead to the absence of a family history. In both instances, a parent carries the mutation but does not have clinical symptoms of the disease.
Figure 2. Pedigree of the Patient.
The patient had two siblings who were alive and well. His father had a history of hypertension. His mother had multiple bilateral renal cysts. One maternal uncle was alive and well. Another maternal uncle had died at 50 years of age from metastatic lung cancer; this uncle reportedly also had a "tumor in the eye" detected at the age of 50 years. Pheo denotes pheochromocytoma. Circles denote female relatives, squares male relatives, the diamond an unknown number of relatives, and symbols with a slash deceased family members.
Table 2. Genetic Testing for Pheochromocytoma.
Thus, in this case, although evaluation of the family history did not assist in making a genetic diagnosis, it does not rule out a hereditary cause. Genetic testing of the peripheral blood is clinically available for each of these conditions.
Dr. Iliopoulos: Up to 25 percent of patients with a pheochromocytoma and no family history of the disease have a germ-line mutation predisposing them to pheochromocytoma,8 most commonly von Hippel–Lindau (VHL) disease, followed by familial paraganglioma and multiple endocrine neoplasia (MEN) type 2. Patients with germ-line mutations have clinical manifestations at a younger age and are more likely to have multifocal or extraadrenal disease than those without mutations. Thus, the young age at onset and the bilateral nature of pheochromocytoma in this patient strongly suggest the presence of a genetic disease predisposing him to pheochromocytoma. We should examine the features of his clinical presentation that may suggest the type of underlying familial disease.
Multiple Endocrine Neoplasia
Pheochromocytoma develops in approximately 50 percent of patients with MEN-2A or MEN-2B; medullary thyroid carcinoma develops in almost all of them. In patients with MEN-2B, medullary thyroid carcinoma develops within the first or second decade of life and precedes the development of pheochromocytoma. Patients with MEN-2A may have pheochromocytoma at the same time as or after medullary thyroid carcinoma. In addition, hyperplasia of the parathyroid gland develops in a large percentage of patients with MEN-2A, and 10 to 30 percent of them have blood changes compatible with the presence of primary hyperparathyroidism.9 Given the absence of medullary thyroid carcinoma and primary hyperparathyroidism in this patient, who already has a history of pheochromocytoma, the diagnosis of MEN is highly unlikely.
Neurofibromatosis
Pheochromocytomas constitute a minor but established feature of neurofibromatosis type 1 (NF1). Pheochromocytoma, juvenile acute myelomonocytic leukemia, malignant peripheral nerve sheath tumors, or sarcoma will develop in approximately 5 percent of patients with NF1. Two of the following seven criteria are required for the clinical diagnosis of NF110: six or more café au lait spots, two or more cutaneous neurofibromas or a plexiform neurofibroma, inguinal or axillary freckles, two or more benign iris hamartomas (Lisch nodules), at least one optic-nerve glioma, dysplasia of sphenoid bone or thinning of the cortex of long bones, and a first-degree relative with NF1. None of these features are present in the patient under discussion; therefore, I would rule out the diagnosis of NF1.
Familial Paraganglioma
Pheochromocytoma may herald the presence of familial paraganglioma, a condition predisposing patients to extraadrenal tumors of chromaffin-positive cells of the parasympathetic nervous system. Four loci of familial paraganglioma have been reported, each one showing autosomal dominant inheritance,11 two of which, 1 and 4, may present exclusively as familial pheochromocytomas or in combination with paraganglioma. The genes responsible for familial paraganglioma types 1, 2, and 4 have been identified as the nucleus-encoded subunits D, C, and B of the mitochondrial enzyme succinate dehydrogenase. The clinical presentation of this patient is compatible with that associated with familial paraganglioma, and we should keep this possibility high in our list of possible diagnoses.
Von Hippel–Lindau Disease
A familial predisposition to pheochromocytoma may occur as a manifestation of autosomal dominant VHL disease. Pheochromocytoma develops in approximately 20 percent of patients with VHL disease, with a mean age at onset in the second decade of life, although such tumors often occur even later. The lesions are symptomatic in 50 percent of the cases, and they may present synchronously, as multifocal and bilateral disease, or metachronously, as appears to be true in this case. They may also present as extraadrenal disease (paragangliomas).
The main complication of VHL disease occurs from central nervous system hemangioblastomas, which are nonmetastasizing vascular tumors.12 Hemangioblastomas often develop in the retina (historically called retinal angiomas) and rarely in locations outside the central nervous system, such as the skin and the liver. They may be also encountered as sporadic, non–VHL-related tumors. VHL-associated hemangioblastomas tend to occur in patients at a younger age (25 years) than the age at which sporadic ones occur (45 years); they present synchronously or metachronously as multiple lesions, and they preferentially develop in the cerebellum (75 percent), spine (20 percent), and brain stem (5 percent). Sporadic hemangioblastomas are mostly single lesions, typically in the spinal cord.
Renal cancer and hemangioblastoma are equally important causes of complications and death from VHL disease.13 These patients have multiple bilateral cysts in the kidneys, and they are at risk for renal-cell carcinoma, exclusively the histologically clear-cell type. Because of the presence of multiple renal cysts, a misdiagnosis of polycystic kidney disease may be made. VHL-associated renal-cell carcinoma is multifocal and bilateral, and it usually appears in the second or third decade of life, although the patients are at risk for the disease throughout their lifetime. In contrast, patients with sporadic renal-cell carcinoma are older (mean age, 50 years), they present with a single tumor of any histologic type, and they have few, if any, kidney cysts.
The clinical presentation of VHL disease also includes cysts and endocrine tumors of the pancreas, liver cysts, and nonmetastasizing papillary cystadenomas of the pancreas, the endolymphatic canal of the middle ear, and the epididymis of male and the adnexal organs of female patients.12,13,14
This patient has a brain-stem lesion that radiographically appears compatible with a hemangioblastoma.14 His mother received a diagnosis of "polycystic kidney disease," and a maternal uncle received a diagnosis of a "tumor in the eye," which could indicate the presence of a retinal hemangioblastoma.15 These observations allow us to suspect clinically that the most likely diagnosis is VHL disease and to test this patient for mutations in the VHL gene.
The VHL gene on chromosome 3p25 consists of three exons16 encoding at least two active isoforms of the VHL disease tumor-suppressor protein (pVHL).17 All patients with VHL have a germ-line inactivating mutation in one VHL allele. VHL gene function is disrupted in all disease-associated tumors, primarily through the deletion of the second, wild-type, allele.
The pVHL tumor-suppressor protein is the substrate receptor of a multiprotein complex that targets specific intracellular protein substrates for ubiquination and destruction by the proteasome.18,19 pVHL binds directly to the regulatory subunits of the hypoxia-inducible transcription factor (HIF) and shortens their intracellular half-life to a few seconds. In the absence of pVHL (as in VHL-associated tumors), HIF is constitutively up-regulated and transcribes a family of growth and angiogenic factors that most likely leads to uncontrolled proliferation of the cell. Constitutive up-regulation of HIF appears necessary and sufficient for the growth of VHL-deficient tumors.20,21,22
Genetic testing for mutations in the VHL gene involves sequencing the three exons and performing Southern blot analysis (Figure 3B). The latter is necessary to identify genomic deletions encompassing the gene and gene inactivation by methylation.23 The advantages of documenting the type of VHL mutation are that family members at risk can be identified and enrolled in clinical surveillance protocols to identify small, asymptomatic, localized tumors, and it permits genotype–phenotype correlation in VHL disease.24 Patients with VHL type 1 disease have gene deletions or specific missense mutations, and they are not at risk for pheochromocytoma. Patients with type 2 disease have mainly (96 percent) specific missense mutations, and pheochromocytoma develops in these patients. They are also at low (type 2A) or high (type 2B) risk for renal-cell carcinoma. A small percentage of patients with VHL (type 2C) will have only pheochromocytoma, without clinical evidence of renal-cell carcinoma or hemangioblastoma. Knowledge of the VHL mutation could therefore tailor the clinical attention and surveillance to the organs at risk and potentially reduce the psychological anxiety and the cost of unnecessary tests.
Figure 3. Adrenalectomy Specimen.
Panel A shows a central brown pheochromocytoma surrounded by compressed, yellow adrenal cortex. Panel B (hematoxylin and eosin) shows that the pheochromocytoma is composed of packages ("zellballen") of uniform cells with surrounding stellate cells and a delicate vascular network.
The procedure in this patient was right adrenalectomy, followed by genetic testing of peripheral-blood leukocytes.
Dr. Othon Iliopoulos's Diagnosis
VHL disease with pheochromocytoma, hemangioblastomas of the medulla and spinal cord, and renal and hepatic cysts.
Pathological Discussion
Dr. David N. Louis: The specimen from the right adrenalectomy showed a well-demarcated, brown tumor within the adrenal gland (Figure 3A). Histologic examination demonstrated a tumor with cellular aggregates known as "zellballen," which are characteristic of pheochromocytoma (Figure 3B). In a few areas, the tumor cells had larger nuclei, with prominent nucleoli and extensive cytoplasm, indicating ganglion-cell differentiation. Malignant features were not observed, and the tumor was contained within the gland.
Dr. Wykrzykowska: The right adrenalectomy was performed without complications. After 24 hours of observation in the intensive care unit, the patient resumed his regular diet and began walking around the surgical floor. His blood pressure was monitored every one or two hours. Treatment with fludrocortisone was added. On the second postoperative day, the patient was found unresponsive at 4 a.m. by the nursing staff and was in cardiac arrest with ventricular fibrillation. Resuscitation was unsuccessful. An autopsy was performed.
Dr. Louis: Autopsy examination revealed lesions characteristic of VHL disease, including brain-stem and spinal cord hemangioblastomas (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org), liver hemangiomas, renal cysts, and a pancreatic endocrine tumor (Figure 2 of the Supplementary Appendix). Three hemangioblastomas were present: in the floor of the fourth ventricle (Figure 4A), in the superficial dorsal right side of the thoracic spinal cord, and in a left lumbar dorsal-nerve root. The fourth ventricular lesion was small, but the lower brain stem was edematous ipsilateral to the hemangioblastoma. The edema was characterized by reactive astrocytes and a vacuolated appearance (Figure 4B). Edema was less prominent in the spinal lesions, but there was a conspicuous mass effect on the adjacent cord (Figure 4C). The hemangioblastomas were highly vascular and contained numerous stromal cells (Figure 4D).
Figure 4. Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosin).
Panel A shows a cross section of the medulla of the brain stem in which edema is apparent ipsilateral to a small fourth ventricular hemangioblastoma (arrow). The dotted line indicates the midline, highlighting the larger size of the left side of the brain stem. Panel B shows edematous areas of the brain stem characterized by reactive astrocytes and small vacuolated regions. Panel C shows a cross section of the thoracic spinal cord in which a small dorsal hemangioblastoma (arrow) is associated with a local mass effect and distortion of the adjacent cord. Panel D shows prominent stromal cells, notable for their prominent vacuolated cytoplasm, as well as a delicate capillary network in the thoracic spinal cord hemangioblastoma.
Hemangioblastomas are composed of stromal cells, endothelial cells, and pericytes, but the stromal cells appear to be the neoplastic component, with chromosomal losses at the VHL locus.25 Recent studies suggest that the stromal cells are related to primitive angiomesenchymal cells that have the potential to differentiate along both hematopoietic and vascular lines.26 This observation may explain the fact that hemangioblastomas often contain foci of extramedullary hematopoiesis.
The stromal cells, as a result of the inactivation of the VHL gene, express large amounts of vascular endothelial growth factor (VEGF).19,27 It is likely that up-regulation of VEGF and, possibly, other angiogenic factors results in the marked vascularity and cyst formation often seen in hemangioblastomas. In this case, the clinical manifestations that led to this patient's presentation may have been due to increased vascular permeability from local VEGF secretion.28
Dr. James R. Stone: Histologic examination of the myocardium revealed multiple microscopic foci of myocardial injury of various ages (Figure 3 of the Supplementary Appendix). There were areas of acute injury (approximately two days old) with contraction-band necrosis and a mixed inflammatory infiltrate, as well as areas of subacute injury (one to two weeks old) with replacement of myocytes by macrophage-rich granulation tissue. In addition, there were multiple microscopic foci of remote injury (more than four weeks old) consisting of collagenous scars. These changes are characteristic of catecholamine-induced toxicity, as observed in patients with pheochromocytoma.29 The myocardial injury present in this patient is sufficient to have caused sudden death by inducing a ventricular dysrhythmia.
Dr. Nancy Lee Harris (Pathology): Dr. Iliopoulos, will you tell us the results of genetic testing?
Dr. Iliopoulos: Genetic testing of the peripheral blood obtained from the patient before death revealed a single base change from G to A at nucleotide 713, resulting in the change in a single amino acid from arginine to glutamine (R167Q). This is a typical mutation in the VHL gene, embedded in the middle of a "hot spot" of VHL disease–associated mutations. Mutations within this area (the alpha domain of the VHL protein) result in the disruption of the interaction between the VHL protein and elongin C, resulting in constitutive overexpression of VHL substrates, including HIF. This is a type 2 gene mutation that is associated with a high risk of renal-cell carcinoma, pheochromocytoma, and hemangioblastoma. The patient's siblings elected to be tested and were found to have no mutation. Parental testing revealed that the mutation was inherited from the mother.
Dr. Harris: Is the occurrence of pheochromocytoma in a child suggestive enough of a familial disease that genetic testing ought to be considered?
Dr. Iliopoulos: Yes. One could make the case that any patient with pheochromocytoma needs to be tested for these diseases, and it is clear that any patient younger than 35 years of age needs to be tested. When this patient presented with his first tumor, the level of risk for a genetic mutation was not as well understood as it is now.
Anatomical Diagnosis
VHL disease with R167Q mutation (type 2), associated with adrenal pheochromocytoma, brain-stem and spinal cord hemangioblastomas, liver hemangiomas, renal cysts, a pancreatic endocrine tumor, and catecholamine-induced myocardial toxicity.
Dr. Stone reports having received consulting fees from MuscleTech. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Cancer Center (O.I., G.C.-S.), and the Departments of Medicine (O.I.), Radiology (R.G.G.), and Pathology (D.N.L., J.R.S.), Massachusetts General Hospital; and the Departments of Medicine (O.I.), Radiology (R.G.G.), and Pathology (D.N.L., J.R.S.), Harvard Medical School.
References
Kudva YC, Sawka AM, Young WF Jr. The laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab 2003;88:4533-4539.
Eisenhofer G, Lenders JWM, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 1999;340:1872-1879.
Neumann HP, Hoegerle S, Manz T, Brenner K, Iliopoulos O. How many pathways to pheochromocytoma? Semin Nephrol 2002;22:89-99.
Schuffenecker I, Ginet N, Goldgar D, et al. Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Am J Hum Genet 1997;60:233-237.
Lazaro C, Ravella A, Gaona A, Volpini V, Estivill X. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med 1994;331:1403-1407.
Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 2002;39:178-183.
Sgambati MT, Stolle C, Choyke PL, et al. Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 2000;66:84-91.
Neumann HPH, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459-1466.
Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-5671.
Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51-57.
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 2003;3:193-202.
Lonser RR, Glenn GM, Walther M, et al. Von Hippel-Lindau disease. Lancet 2003;361:2059-2067.
Maher ER, Kaelin WG Jr. Von Hippel-Lindau disease. Medicine (Baltimore) 1997;76:381-391.
Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. Von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 1995;194:629-642.
Wittebol-Post D, Hes FJ, Lips CJM. The eye in Von Hippel-Lindau disease: long term follow up of screening and treatment recommendations. J Intern Med 1998;243:555-561.
Latif F, Tory K, Gnarra J, et al. Identification of the Von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317-1320.
Iliopoulos O. VHL disease: genetic and clinical observations. In: Dahia PML, Eng C, eds. Genetic disorders of endocrine neoplasia. Vol. 28. Basel, Switzerland: Karger, 2001:131-66.
Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 2004;10:6290S-6295S.
Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005;353:2477-2490.
Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237-246.
Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL–/– tumors. Mol Cancer Res 2004;2:89-95.
Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003;1:E83-E83.
Stolle C, Glenn G, Zbar B, et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998;12:417-423.
Zbar B, Kishida T, Chen F, et al. Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996;8:348-357.
Lee JY, Dong SM, Park WS, et al. Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res 1998;58:504-508.
Vortmeyer AO, Frank S, Jeong SY, et al. Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res 2003;63:7051-7055.
Wizigmann-Voos S, Breier G, Risau W, Plate KH. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 1995;55:1358-1364.
Provias J, Claffey K, delAguila L, Lau N, Feldkamp M, Guha A. Meningiomas: role of vascular endothelial growth factor/ vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 1997;40:1016-1026.
van Vliet PD, Burchell HB, Titus JL. Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966;274:1102-1108.(Othon Iliopoulos, M.D., G)
Dr. Joanna J. Wykrzykowska (Medicine): A 36-year-old man was admitted to the hospital because of a mass in the right adrenal gland. The patient had been well until seven months before admission, when numbness developed in his left arm, one week after he had been in a motor vehicle accident. He saw a chiropractor, who ordered magnetic resonance imaging (MRI) of his cervical spine, which disclosed a cystic lesion in the medulla. During the evaluation he was noted to have hypertension. Atenolol and nortriptyline were prescribed, and three and a half weeks before admission, he was referred to the surgical clinic of this hospital.
At that time, he reported profuse sweating at night (requiring a change of sheets), palpitations three to five times per day, and insomnia. On examination, the blood pressure was 170/110 mm Hg. MRI of the abdomen three weeks before admission revealed a right adrenal mass, 2.3 by 1.9 cm, with homogeneous enhancement in the arterial phase. There was a complex cyst, 2 by 1 cm, in the left kidney with enhancing septations. There were multiple lesions — apparently hemangiomas — in the liver that appeared bright on T2-weighted images, the largest being 2.4 by 2 cm. metaiodobenzylguanidine (MIBG) scanning on the same day showed a focus of increased radiotracer uptake in the right upper quadrant of the abdomen, superior and medial to the right kidney. The results of routine blood and urine chemical tests and a complete blood count were normal. Urine and serum catecholamine levels are shown in Table 1. MRI of the brain one week later disclosed a right medullary tumor, 1.3 cm in diameter, with a central cystic component that contained a small enhancing nodule along the posterior wall and a solid, nonenhancing component that was isointense relative to brain tissue on T1-weighted and T2-weighted images.
Table 1. Catecholamine Levels.
Twelve days before admission the patient's blood pressure was 190/120 mm Hg. Treatment with terazosin and phenoxybenzamine was begun. Five days before admission, nerve-conduction studies and needle electromyographic examination of the left deltoid, biceps, and flexor carpi radialis were normal. A left cervical radiculopathy could not be ruled out since the patient could not tolerate a full examination including cervical paraspinal muscles. One week later he was admitted to this hospital.
An appendectomy had been performed at the age of 12 years, at which time hypertension was noted; subsequent evaluation disclosed a left adrenal pheochromocytoma, which was resected. The patient received no further medical care until he had a motor vehicle accident. He had no allergies. He smoked half a pack of cigarettes per day and drank alcohol. His mother had polycystic kidney disease. His father had had hypertension since his 50s. His siblings (a 32-year-old sister and a twin brother) and his 15-year-old daughter were healthy. His paternal grandmother had died of a heart attack in her 60s, and his paternal grandfather had died of a stroke in his 70s. His maternal grandfather had died of emphysema. His maternal grandmother had died at the age of 90.
On examination the patient was an anxious-appearing young man. The blood pressure was 145/100 mm Hg and the pulse 64 beats per minute. There was no plethora or proptosis. The thyroid was normal in size and consistency. The heart and lungs were normal. The abdomen was soft and nontender without organomegaly or palpable masses. There was no peripheral edema. Neurologic examination revealed that the strength was 4/4 in the hands and legs, with good muscle bulk, slightly asymmetric reflexes (1+ on the right and 2+ on the left), and decreased proprioception and sensation to touch and temperature in the left arm but no dysmetria. Ophthalmologic examination showed a right retinal hemangioma in the superotemporal periphery, with a large vein leading into it.
Results on routine blood chemical tests and a complete blood count were normal. MRI of the spine revealed a small focal area of enhancement posterior to the spinal cord just to the right of the midline at the level of the T12 vertebral body; the remainder of the examination was normal.
Terazosin was discontinued; increasing doses of phenoxybenzamine were administered, with intravenous normal saline. On the 14th hospital day the blood pressure was 146/80 mm Hg. Phenoxybenzamine was discontinued, and intravenous hydrocortisone was begun; a procedure was performed.
Differential Diagnosis
Dr. Othon Iliopoulos: May we see the imaging studies?
Dr. R. Gilberto Gonzalez: MRI of the abdomen revealed a 2-cm mass located just above the right kidney in the expected location of the adrenal gland. On axial images we noted multiple cystic abnormalities in the liver as well as in the kidney, one of which was complex and enhanced with contrast material (Figure 1A). Nuclear-medicine scanning (Figure 1B) after the administration of MIBG, which is avidly taken up by tissues that secrete catecholamines, showed an area of uptake inferomedial to the liver and superior to the right kidney. MRI of the brain revealed a cystic mass in the dorsal medulla, the posterior aspect of which enhanced intensely after administration of contrast material (Figure 1C and 1D).
Figure 1. Radiologic Images.
MRI of the abdomen three weeks before admission (Panel A) revealed multiple bright lesions in the liver (curved arrow) and kidneys (straight arrows) on T2-weighted images. A posterior view from the MIBG scintigraphic scan (Panel B) demonstrates abnormal uptake in the right upper quadrant of the abdomen below the liver (arrow). MRI of the brain (Panel C) revealed a cystic mass in the dorsal medulla (arrow), with a posterior nodule that enhanced intensely after the administration of contrast material (Panel D, arrow).
Dr. Iliopoulos: This 36-year-old man with a childhood history of pheochromocytoma presented with clinical manifestations of elevated catecholamine levels. Plasma metanephrine and normetanephrine levels are 97 percent sensitive and 96 percent specific for the identification of pheochromocytoma in patients with a genetic predisposition to pheochromocytoma.1,2 Thus, this patient's clinical characteristics are associated with a high probability of recurrent pheochromocytoma. To identify the location of his pheochromocytoma, MIBG scanning was performed. When the sensitivity and specificity of different imaging methods for pheochromocytoma have been compared,3 MIBG nuclear scanning appears to have the highest sensitivity (95 percent) and specificity (97 percent); the results are similar to those of MRI. The advantage of MIBG scanning over MRI is that it offers a total-body survey for the detection of pheochromocytoma. In this patient, both MRI and MIBG imaging clearly identified a pheochromocytoma in the right adrenal gland; this recurrence of pheochromocytoma raised the possibility of an underlying hereditary condition and prompted us to conduct a genetic evaluation.
Ms. Gayun Chan-Smutko: As part of the genetic-counseling process for this family, a four-generation pedigree was obtained (Figure 2). Based on this information, the family history was apparently not a contributor to the differential diagnosis. Despite the absence of a clear familial syndrome, five distinct autosomal dominant hereditary syndromes with pheochromocytoma as a component tumor need to be considered (Table 2).4,5,6,7 In all these syndromes, between 5 and 50 percent of patients have no family history of pheochromocytoma. Several factors can contribute to the absence of a family history: a new mutation that occurred spontaneously during gametogenesis in one of the parents, a germ-line mosaicism in one of the parents, or a new mutation in the embryo. Reduced penetrance (in which a proportion of persons carrying a mutation express no features of the expected phenotype) and variable expression (in which the degree of severity of symptoms differs among family members) can also lead to the absence of a family history. In both instances, a parent carries the mutation but does not have clinical symptoms of the disease.
Figure 2. Pedigree of the Patient.
The patient had two siblings who were alive and well. His father had a history of hypertension. His mother had multiple bilateral renal cysts. One maternal uncle was alive and well. Another maternal uncle had died at 50 years of age from metastatic lung cancer; this uncle reportedly also had a "tumor in the eye" detected at the age of 50 years. Pheo denotes pheochromocytoma. Circles denote female relatives, squares male relatives, the diamond an unknown number of relatives, and symbols with a slash deceased family members.
Table 2. Genetic Testing for Pheochromocytoma.
Thus, in this case, although evaluation of the family history did not assist in making a genetic diagnosis, it does not rule out a hereditary cause. Genetic testing of the peripheral blood is clinically available for each of these conditions.
Dr. Iliopoulos: Up to 25 percent of patients with a pheochromocytoma and no family history of the disease have a germ-line mutation predisposing them to pheochromocytoma,8 most commonly von Hippel–Lindau (VHL) disease, followed by familial paraganglioma and multiple endocrine neoplasia (MEN) type 2. Patients with germ-line mutations have clinical manifestations at a younger age and are more likely to have multifocal or extraadrenal disease than those without mutations. Thus, the young age at onset and the bilateral nature of pheochromocytoma in this patient strongly suggest the presence of a genetic disease predisposing him to pheochromocytoma. We should examine the features of his clinical presentation that may suggest the type of underlying familial disease.
Multiple Endocrine Neoplasia
Pheochromocytoma develops in approximately 50 percent of patients with MEN-2A or MEN-2B; medullary thyroid carcinoma develops in almost all of them. In patients with MEN-2B, medullary thyroid carcinoma develops within the first or second decade of life and precedes the development of pheochromocytoma. Patients with MEN-2A may have pheochromocytoma at the same time as or after medullary thyroid carcinoma. In addition, hyperplasia of the parathyroid gland develops in a large percentage of patients with MEN-2A, and 10 to 30 percent of them have blood changes compatible with the presence of primary hyperparathyroidism.9 Given the absence of medullary thyroid carcinoma and primary hyperparathyroidism in this patient, who already has a history of pheochromocytoma, the diagnosis of MEN is highly unlikely.
Neurofibromatosis
Pheochromocytomas constitute a minor but established feature of neurofibromatosis type 1 (NF1). Pheochromocytoma, juvenile acute myelomonocytic leukemia, malignant peripheral nerve sheath tumors, or sarcoma will develop in approximately 5 percent of patients with NF1. Two of the following seven criteria are required for the clinical diagnosis of NF110: six or more café au lait spots, two or more cutaneous neurofibromas or a plexiform neurofibroma, inguinal or axillary freckles, two or more benign iris hamartomas (Lisch nodules), at least one optic-nerve glioma, dysplasia of sphenoid bone or thinning of the cortex of long bones, and a first-degree relative with NF1. None of these features are present in the patient under discussion; therefore, I would rule out the diagnosis of NF1.
Familial Paraganglioma
Pheochromocytoma may herald the presence of familial paraganglioma, a condition predisposing patients to extraadrenal tumors of chromaffin-positive cells of the parasympathetic nervous system. Four loci of familial paraganglioma have been reported, each one showing autosomal dominant inheritance,11 two of which, 1 and 4, may present exclusively as familial pheochromocytomas or in combination with paraganglioma. The genes responsible for familial paraganglioma types 1, 2, and 4 have been identified as the nucleus-encoded subunits D, C, and B of the mitochondrial enzyme succinate dehydrogenase. The clinical presentation of this patient is compatible with that associated with familial paraganglioma, and we should keep this possibility high in our list of possible diagnoses.
Von Hippel–Lindau Disease
A familial predisposition to pheochromocytoma may occur as a manifestation of autosomal dominant VHL disease. Pheochromocytoma develops in approximately 20 percent of patients with VHL disease, with a mean age at onset in the second decade of life, although such tumors often occur even later. The lesions are symptomatic in 50 percent of the cases, and they may present synchronously, as multifocal and bilateral disease, or metachronously, as appears to be true in this case. They may also present as extraadrenal disease (paragangliomas).
The main complication of VHL disease occurs from central nervous system hemangioblastomas, which are nonmetastasizing vascular tumors.12 Hemangioblastomas often develop in the retina (historically called retinal angiomas) and rarely in locations outside the central nervous system, such as the skin and the liver. They may be also encountered as sporadic, non–VHL-related tumors. VHL-associated hemangioblastomas tend to occur in patients at a younger age (25 years) than the age at which sporadic ones occur (45 years); they present synchronously or metachronously as multiple lesions, and they preferentially develop in the cerebellum (75 percent), spine (20 percent), and brain stem (5 percent). Sporadic hemangioblastomas are mostly single lesions, typically in the spinal cord.
Renal cancer and hemangioblastoma are equally important causes of complications and death from VHL disease.13 These patients have multiple bilateral cysts in the kidneys, and they are at risk for renal-cell carcinoma, exclusively the histologically clear-cell type. Because of the presence of multiple renal cysts, a misdiagnosis of polycystic kidney disease may be made. VHL-associated renal-cell carcinoma is multifocal and bilateral, and it usually appears in the second or third decade of life, although the patients are at risk for the disease throughout their lifetime. In contrast, patients with sporadic renal-cell carcinoma are older (mean age, 50 years), they present with a single tumor of any histologic type, and they have few, if any, kidney cysts.
The clinical presentation of VHL disease also includes cysts and endocrine tumors of the pancreas, liver cysts, and nonmetastasizing papillary cystadenomas of the pancreas, the endolymphatic canal of the middle ear, and the epididymis of male and the adnexal organs of female patients.12,13,14
This patient has a brain-stem lesion that radiographically appears compatible with a hemangioblastoma.14 His mother received a diagnosis of "polycystic kidney disease," and a maternal uncle received a diagnosis of a "tumor in the eye," which could indicate the presence of a retinal hemangioblastoma.15 These observations allow us to suspect clinically that the most likely diagnosis is VHL disease and to test this patient for mutations in the VHL gene.
The VHL gene on chromosome 3p25 consists of three exons16 encoding at least two active isoforms of the VHL disease tumor-suppressor protein (pVHL).17 All patients with VHL have a germ-line inactivating mutation in one VHL allele. VHL gene function is disrupted in all disease-associated tumors, primarily through the deletion of the second, wild-type, allele.
The pVHL tumor-suppressor protein is the substrate receptor of a multiprotein complex that targets specific intracellular protein substrates for ubiquination and destruction by the proteasome.18,19 pVHL binds directly to the regulatory subunits of the hypoxia-inducible transcription factor (HIF) and shortens their intracellular half-life to a few seconds. In the absence of pVHL (as in VHL-associated tumors), HIF is constitutively up-regulated and transcribes a family of growth and angiogenic factors that most likely leads to uncontrolled proliferation of the cell. Constitutive up-regulation of HIF appears necessary and sufficient for the growth of VHL-deficient tumors.20,21,22
Genetic testing for mutations in the VHL gene involves sequencing the three exons and performing Southern blot analysis (Figure 3B). The latter is necessary to identify genomic deletions encompassing the gene and gene inactivation by methylation.23 The advantages of documenting the type of VHL mutation are that family members at risk can be identified and enrolled in clinical surveillance protocols to identify small, asymptomatic, localized tumors, and it permits genotype–phenotype correlation in VHL disease.24 Patients with VHL type 1 disease have gene deletions or specific missense mutations, and they are not at risk for pheochromocytoma. Patients with type 2 disease have mainly (96 percent) specific missense mutations, and pheochromocytoma develops in these patients. They are also at low (type 2A) or high (type 2B) risk for renal-cell carcinoma. A small percentage of patients with VHL (type 2C) will have only pheochromocytoma, without clinical evidence of renal-cell carcinoma or hemangioblastoma. Knowledge of the VHL mutation could therefore tailor the clinical attention and surveillance to the organs at risk and potentially reduce the psychological anxiety and the cost of unnecessary tests.
Figure 3. Adrenalectomy Specimen.
Panel A shows a central brown pheochromocytoma surrounded by compressed, yellow adrenal cortex. Panel B (hematoxylin and eosin) shows that the pheochromocytoma is composed of packages ("zellballen") of uniform cells with surrounding stellate cells and a delicate vascular network.
The procedure in this patient was right adrenalectomy, followed by genetic testing of peripheral-blood leukocytes.
Dr. Othon Iliopoulos's Diagnosis
VHL disease with pheochromocytoma, hemangioblastomas of the medulla and spinal cord, and renal and hepatic cysts.
Pathological Discussion
Dr. David N. Louis: The specimen from the right adrenalectomy showed a well-demarcated, brown tumor within the adrenal gland (Figure 3A). Histologic examination demonstrated a tumor with cellular aggregates known as "zellballen," which are characteristic of pheochromocytoma (Figure 3B). In a few areas, the tumor cells had larger nuclei, with prominent nucleoli and extensive cytoplasm, indicating ganglion-cell differentiation. Malignant features were not observed, and the tumor was contained within the gland.
Dr. Wykrzykowska: The right adrenalectomy was performed without complications. After 24 hours of observation in the intensive care unit, the patient resumed his regular diet and began walking around the surgical floor. His blood pressure was monitored every one or two hours. Treatment with fludrocortisone was added. On the second postoperative day, the patient was found unresponsive at 4 a.m. by the nursing staff and was in cardiac arrest with ventricular fibrillation. Resuscitation was unsuccessful. An autopsy was performed.
Dr. Louis: Autopsy examination revealed lesions characteristic of VHL disease, including brain-stem and spinal cord hemangioblastomas (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org), liver hemangiomas, renal cysts, and a pancreatic endocrine tumor (Figure 2 of the Supplementary Appendix). Three hemangioblastomas were present: in the floor of the fourth ventricle (Figure 4A), in the superficial dorsal right side of the thoracic spinal cord, and in a left lumbar dorsal-nerve root. The fourth ventricular lesion was small, but the lower brain stem was edematous ipsilateral to the hemangioblastoma. The edema was characterized by reactive astrocytes and a vacuolated appearance (Figure 4B). Edema was less prominent in the spinal lesions, but there was a conspicuous mass effect on the adjacent cord (Figure 4C). The hemangioblastomas were highly vascular and contained numerous stromal cells (Figure 4D).
Figure 4. Findings in the Central Nervous System at Autopsy (Luxol Fast Blue–Hematoxylin and Eosin).
Panel A shows a cross section of the medulla of the brain stem in which edema is apparent ipsilateral to a small fourth ventricular hemangioblastoma (arrow). The dotted line indicates the midline, highlighting the larger size of the left side of the brain stem. Panel B shows edematous areas of the brain stem characterized by reactive astrocytes and small vacuolated regions. Panel C shows a cross section of the thoracic spinal cord in which a small dorsal hemangioblastoma (arrow) is associated with a local mass effect and distortion of the adjacent cord. Panel D shows prominent stromal cells, notable for their prominent vacuolated cytoplasm, as well as a delicate capillary network in the thoracic spinal cord hemangioblastoma.
Hemangioblastomas are composed of stromal cells, endothelial cells, and pericytes, but the stromal cells appear to be the neoplastic component, with chromosomal losses at the VHL locus.25 Recent studies suggest that the stromal cells are related to primitive angiomesenchymal cells that have the potential to differentiate along both hematopoietic and vascular lines.26 This observation may explain the fact that hemangioblastomas often contain foci of extramedullary hematopoiesis.
The stromal cells, as a result of the inactivation of the VHL gene, express large amounts of vascular endothelial growth factor (VEGF).19,27 It is likely that up-regulation of VEGF and, possibly, other angiogenic factors results in the marked vascularity and cyst formation often seen in hemangioblastomas. In this case, the clinical manifestations that led to this patient's presentation may have been due to increased vascular permeability from local VEGF secretion.28
Dr. James R. Stone: Histologic examination of the myocardium revealed multiple microscopic foci of myocardial injury of various ages (Figure 3 of the Supplementary Appendix). There were areas of acute injury (approximately two days old) with contraction-band necrosis and a mixed inflammatory infiltrate, as well as areas of subacute injury (one to two weeks old) with replacement of myocytes by macrophage-rich granulation tissue. In addition, there were multiple microscopic foci of remote injury (more than four weeks old) consisting of collagenous scars. These changes are characteristic of catecholamine-induced toxicity, as observed in patients with pheochromocytoma.29 The myocardial injury present in this patient is sufficient to have caused sudden death by inducing a ventricular dysrhythmia.
Dr. Nancy Lee Harris (Pathology): Dr. Iliopoulos, will you tell us the results of genetic testing?
Dr. Iliopoulos: Genetic testing of the peripheral blood obtained from the patient before death revealed a single base change from G to A at nucleotide 713, resulting in the change in a single amino acid from arginine to glutamine (R167Q). This is a typical mutation in the VHL gene, embedded in the middle of a "hot spot" of VHL disease–associated mutations. Mutations within this area (the alpha domain of the VHL protein) result in the disruption of the interaction between the VHL protein and elongin C, resulting in constitutive overexpression of VHL substrates, including HIF. This is a type 2 gene mutation that is associated with a high risk of renal-cell carcinoma, pheochromocytoma, and hemangioblastoma. The patient's siblings elected to be tested and were found to have no mutation. Parental testing revealed that the mutation was inherited from the mother.
Dr. Harris: Is the occurrence of pheochromocytoma in a child suggestive enough of a familial disease that genetic testing ought to be considered?
Dr. Iliopoulos: Yes. One could make the case that any patient with pheochromocytoma needs to be tested for these diseases, and it is clear that any patient younger than 35 years of age needs to be tested. When this patient presented with his first tumor, the level of risk for a genetic mutation was not as well understood as it is now.
Anatomical Diagnosis
VHL disease with R167Q mutation (type 2), associated with adrenal pheochromocytoma, brain-stem and spinal cord hemangioblastomas, liver hemangiomas, renal cysts, a pancreatic endocrine tumor, and catecholamine-induced myocardial toxicity.
Dr. Stone reports having received consulting fees from MuscleTech. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Cancer Center (O.I., G.C.-S.), and the Departments of Medicine (O.I.), Radiology (R.G.G.), and Pathology (D.N.L., J.R.S.), Massachusetts General Hospital; and the Departments of Medicine (O.I.), Radiology (R.G.G.), and Pathology (D.N.L., J.R.S.), Harvard Medical School.
References
Kudva YC, Sawka AM, Young WF Jr. The laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab 2003;88:4533-4539.
Eisenhofer G, Lenders JWM, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 1999;340:1872-1879.
Neumann HP, Hoegerle S, Manz T, Brenner K, Iliopoulos O. How many pathways to pheochromocytoma? Semin Nephrol 2002;22:89-99.
Schuffenecker I, Ginet N, Goldgar D, et al. Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Am J Hum Genet 1997;60:233-237.
Lazaro C, Ravella A, Gaona A, Volpini V, Estivill X. Neurofibromatosis type 1 due to germ-line mosaicism in a clinically normal father. N Engl J Med 1994;331:1403-1407.
Baysal BE, Willett-Brozick JE, Lawrence EC, et al. Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 2002;39:178-183.
Sgambati MT, Stolle C, Choyke PL, et al. Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 2000;66:84-91.
Neumann HPH, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459-1466.
Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-5671.
Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51-57.
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 2003;3:193-202.
Lonser RR, Glenn GM, Walther M, et al. Von Hippel-Lindau disease. Lancet 2003;361:2059-2067.
Maher ER, Kaelin WG Jr. Von Hippel-Lindau disease. Medicine (Baltimore) 1997;76:381-391.
Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. Von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 1995;194:629-642.
Wittebol-Post D, Hes FJ, Lips CJM. The eye in Von Hippel-Lindau disease: long term follow up of screening and treatment recommendations. J Intern Med 1998;243:555-561.
Latif F, Tory K, Gnarra J, et al. Identification of the Von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317-1320.
Iliopoulos O. VHL disease: genetic and clinical observations. In: Dahia PML, Eng C, eds. Genetic disorders of endocrine neoplasia. Vol. 28. Basel, Switzerland: Karger, 2001:131-66.
Kaelin WG Jr. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res 2004;10:6290S-6295S.
Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005;353:2477-2490.
Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell 2002;1:237-246.
Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL–/– tumors. Mol Cancer Res 2004;2:89-95.
Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003;1:E83-E83.
Stolle C, Glenn G, Zbar B, et al. Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998;12:417-423.
Zbar B, Kishida T, Chen F, et al. Germline mutations in the von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996;8:348-357.
Lee JY, Dong SM, Park WS, et al. Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas. Cancer Res 1998;58:504-508.
Vortmeyer AO, Frank S, Jeong SY, et al. Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res 2003;63:7051-7055.
Wizigmann-Voos S, Breier G, Risau W, Plate KH. Up-regulation of vascular endothelial growth factor and its receptors in von Hippel-Lindau disease-associated and sporadic hemangioblastomas. Cancer Res 1995;55:1358-1364.
Provias J, Claffey K, delAguila L, Lau N, Feldkamp M, Guha A. Meningiomas: role of vascular endothelial growth factor/ vascular permeability factor in angiogenesis and peritumoral edema. Neurosurgery 1997;40:1016-1026.
van Vliet PD, Burchell HB, Titus JL. Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966;274:1102-1108.(Othon Iliopoulos, M.D., G)